Rheumatic Diseases Clinical Trials Roundtable Summary

Introduction

This roundtable was convened as part of a larger NIAMS effort to assess its support of clinical trials across the Institute’s mission areas. Goals include identifying needs and opportunities, as well as finding key steps for evaluating trials and the significance of individual studies in the broader context of future clinical needs. There were prior discussions on the subject at the 2009 NIAMS Scientific Retreat and with the NIAMS Advisory Council. A Council subcommittee is being created for further developments. Roundtable attendees canvassed their relevant communities in advance, to bring more than their own opinions to the meeting.

Current needs

The variation of symptoms and progression of rheumatic diseases across the patient populations exemplifies the complexity of these illnesses. Current biologic treatments for rheumatoid arthritis (RA) inhibit specific pathways, but future development of tailored treatments will rely on knowledge of disease mechanisms, molecular characterization of disease subtypes, and genetic underpinnings of individual responses and adverse reactions to drugs. This approach is also appropriate for less common diseases, such as scleroderma, which are currently treated with agents that act upon general systems of inflammation or autoimmunity, rather than on disease-specific pathways. Biomarker development is integral to these analyses, as well as measuring clinical responses in various patient populations.

The translation of laboratory research results to potential clinical use requires pre-clinical, proof-of-concept, and pilot studies. The pharmaceutical industry conducts the range of research required for drug development, but focuses on clinical trials that inform the Food and Drug Administration’s (FDA) drug approval process. In contrast, the NIH is interested in clinical trials related to mechanisms of action, personalized medicine, and comparative effectiveness research.

Although trials that address scientific questions are important for advancing knowledge and finding new treatments, they can be complemented by studies on specific clinical care and unmet patient needs. For example, simple, inexpensive pharmacologic and non-pharmacologic (e.g., exercise) therapies for pain may have significant impact on a broad range of illnesses. Comparative effectiveness research is critical to the nation’s healthcare needs. Head-to-head comparisons of therapies can be tested in clinical trials, but efficient and influential studies can also be conducted by analyzing data from healthcare databases.

Many drug approval trials employ placebo control designs (generally in combination with a baseline therapy, such as methotrexate for RA), in order to demonstrate a greater clinical effect, but the use of active comparator trials (e.g., against the current standard-of-care) would be of greater value to evaluation of new therapies. Often, industry-sponsored trials focus on cohorts of patients with the most severe disease subtype. However, the majority of patients are affected by mild to moderate symptoms, which are important to address in future clinical trials. The effects of tapering or terminating treatments may also be investigated, as well as the potential for combination therapies and the clinical impact of comorbidities and concurrent medications.

Registries and databases, with linked biorepositories, can contribute to phenotyping and associated biomarker development efforts. This infrastructure could also support longitudinal studies of response to treatment, which are important in assessing the impact of long-term health status, drug exposure, and management of chronic rheumatic diseases, particularly those beginning in childhood.

At present, European countries provide the most substantive information for long-term monitoring of rheumatic diseases, which is fostered by nationalized healthcare and centralized databases. Data from U.S. patient populations are still needed because the differences in healthcare systems diminish the utility of outcomes from other countries. Compatibility with other countries’ systems would enhance current collaborations, and enable future collective efforts. Databases must be useful and accessible to community physicians, who may play larger roles in future clinical trials. High standards must be maintained, to assure data quality for the entire research community.

Future needs: obtaining input for important questions

The NIAMS seeks methods for receiving continuous information concerning the needs of the clinical research, clinician, and patient communities. Face-to-face roundtables and consensus conferences with stakeholders, such as clinical investigators, professional groups, clinicians, and patient groups, are useful approaches. It is particularly important to include practicing physicians and patients, because of their awareness of the daily clinical problems and essential participation in future clinical trials. Contributions from industry representatives and regular interactions with the FDA would also be valuable, for understanding emerging trends and challenges, as well as identifying gaps and opportunities. Other research organizations and networks have developed mechanisms for obtaining input, which could be used, as well as the relevant information that they have gathered through these processes. Community input on future research topics can be solicited, sometimes for a specific clinical need. Competitive funding opportunities can be developed from these concepts, which could encompass single or multiple clinical research priorities.

Opportunities

From prior investments by the NIAMS and other organizations, there is an existing infrastructure of registries, databases, and biorepositories that can be sustained economically for future research needs. U.S. Veterans Health Administration databases would be a valuable resource for long-term treatment and follow-up studies. Access to similar information, data, and samples from industry-sponsored trials would be very beneficial to academic researchers, if ownership and storage issues could be overcome. There is a robust capability in the U.S. research community for biomarker studies, disease subtyping, and redefinition of disease outcomes, for the efficient testing of new therapies, as they emerge.

Many rheumatic disease clinical trials are hampered by small participant numbers, particularly for disease subtypes, rare diseases, genetic profiling, and biomarker studies. Current international collaborations for many rheumatic diseases, including vasculitis and scleroderma, increase cohort sizes for sufficient statistical power to provide useful outcomes.

ResearchMatch (http://www.researchmatch.org) is a new website created by collaborating academic medical centers in the Clinical and Translational Science Awards network (funded by the National Center for Research Resources), that will pair people interested in participating in clinical trials across the country with appropriate clinical trials. This activity is expected to facilitate clinical trial enrollment for a wide range of disease studies.

The essential partnerships with academic medical centers require attention to credit for multiple principal investigators, relevant publication policies, sustained funding, and inclusion of junior investigators. The NIH provides many funding mechanisms to support the next generation of clinical investigators. The timeline for publishing results from clinical trials can be quite long, and not optimal for a junior clinical investigator’s career development. However, the day-to-day participation and the opportunities to lead ancillary studies provide valuable experience and potential authorship.

The pharmaceutical industry is interested in the development of markers for use in diagnosis and identifying patients who respond to selected therapies. These provide opportunities for partnerships with academic researchers in a precompetitive atmosphere.

Prioritization

Limited resources encourage the development of predictors of successful trials. Factors contributing to failed trials include poor enrollment and poor data. The NIAMS will be requiring completion of a grant-supported planning phase, followed by a cooperative grant mechanism, for all clinical trials it funds. To develop realistic enrollment plans for the larger trial, investigators can utilize mock enrollment periods, to determine prospective numbers of eligible and actual participants. Reviewing enrollment logs from similar trials can indicate why participants did not qualify initially or left a trial before completion. Including community physicians early in trial planning can enhance their involvement and commitment to reaching enrollment goals. Enlisting a large number of research sites can fill enrollment gaps created by locations with low or no recruitment. Addressing administrative issues to increase efficiency in research site initiation, such as facilitating institutional review board (IRB) approval and standardizing reimbursement costs in subcontracts, can also aid enrollment goals. A successful track record for investigators or research teams is a useful indicator of future success. However, it is also important for projects to involve junior investigators.

Future studies can take advantage of high levels of research activity around the development of new therapeutics for common diseases, which are driven by market forces. Clinical trials on common therapeutic targets, identified through disease mechanisms, can inform the understanding and treatment of multiple diseases. Therapeutic studies for rare diseases can be designed to have broader implications beyond the small patient population under investigation, such as insights into pre-eclampsia from studies on lupus and pregnancy.

Comparative effectiveness research is viewed as a critical subject for U.S. healthcare. From the perspective of the patient community, trials addressing quality-of-life treatments are needed for intractable conditions with distant goals of remission. Gauging patient-reported outcomes (PROs) is an essential component of both efforts. The NIH Roadmap for Medical Research’s Patient-Reported Outcomes Measurement Information System (PROMIS [http://www.nihpromis.org]) initiative aims to assess PROs more precisely and efficiently, for a broad array of chronic diseases.

Outcomes

Evaluating the impact of a clinical trial can contribute to designing future research agendas. A trial’s influence may be demonstrated when professional societies consider the findings in the development of practice guidelines, and identify knowledge gaps for future research in the process. Concrete indicators include an impact on evidence-based third party reimbursement, or adoption by large healthcare systems, such as the U.S. Veterans Health Administration. Professional societies have conducted surveys of physicians, concerning which published studies have changed their practice of medicine. It is important to disseminate relevant clinical information from clinical trials to physicians and other healthcare providers, and facilitate the further distribution of this knowledge to the patient community.

Our Mission

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.